Abstract 587: ACLX-002, a novel CD123-targeted universal CAR-T cell therapy for relapsed or refractory acute myeloid leukemia that can be activated and silenced <i>in vivo</i> with soluble protein adapters in a dose dependent manner
Authors: Justin P. Edwards, Liubov Zaritskaya, Jeff Swers, Sinnie Ng, Jenny Mu, Alexandra Witter, Laurene Cheung, Samantha McCullough, David LaFleur, David Hilbert, David Tice
Journal: Cancer Research (2022)

Abstract Genetically engineered T cells have demonstrated great promise in the treatment of hematologic malignancies including Acute Lymphocytic Leukemia, Non-Hodgkin’s lymphoma and Multiple Myeloma. However, those successes are often associated with serious dose-limiting adverse events including cytokine release syndrome (CRS) and immune effector-cell associated neurotoxicity syndrome (ICANS), as well as frequent tumor relapse. Specifically, in AML, there is a need for controllable and adaptable cellular therapeutics that can address intra- and inter- patient disease heterogeneity and off-target antigen expression that contribute to these dose-limiting adverse events. Herein, we report a novel T cell therapy, ACLX-002, comprised of a soluble tumor targeting protein (SPRX002) that specifically binds CD123-expressing AML cells and targets those cells for destruction by ex vivo transduced T cells known as Antigen Receptor Complex (ARC) T cells. Functional in vitro studies of ARC-T cells produced from healthy subjects demonstrated SPRX002 dose-dependent cytokine production, T cell proliferation, and cytotoxic activity of co-cultured CD123-expressing cancer cell lines. The cytolytic machinery of the ARC-T cells is only activated when the tri-complex of the ARC-T cell, SPRX002, and CD123-expressing cell is fully formed. ACLX-002 also demonstrated dose- and schedule-dependent in vivo efficacy in both the MOLM14 and MV4-11 disseminated CD123-expressing tumor models in NSG immunocompromised mice, as well as multiple AML patient derived xenograft models. A single dose of 5 x 106 ARC-T cells together with SPRX002 doses of 0.3 mg/kg daily were able to eliminate measurable tumor burden that was similar to a CD123-directed traditional CAR-T that uses the same CD123-binding domain as SPRX002. Furthermore, the in vivo efficacy was not limited by the expression of CD123 on donor T cells, an attribute that is induced by in vitro activation and expansion of ARC-T cells. The data support the paradigm that ARC-T cells can be activated and silenced by controlling the dose and schedule of administered SPRX002, which may improve the safety and effectiveness of T cell therapy. Citation Format: Justin P. Edwards, Liubov Zaritskaya, Jeff Swers, Sinnie Ng, Jenny Mu, Alexandra Witter, Laurene Cheung, Samantha McCullough, David LaFleur, David Hilbert, David Tice. ACLX-002, a novel CD123-targeted universal CAR-T cell therapy for relapsed or refractory acute myeloid leukemia that can be activated and silenced in vivo with soluble protein adapters in a dose dependent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 587.